Congenital human cytomegalovirus (HCMV) infection is the most common viral infection a leading non- genetic cause of sensorineural hearing loss and other neurological sequelae. Although prevention of this intrauterine infection remains a high priority for vaccine development, currently no vaccine is available and early clinical trials have had only limited success. Understanding the role of antiviral antibody responses in limiting virus transmission is a necessary prerequisite for the successful design of an efficacious vaccine. Since the characteristics of antiviral immune responses that limit HCMV acquisition are unknown, identification of potentially protective responses in the normal host will continue to rely on the empiricism vaccine trials with candidate immunogens selected by a combination of good faith and limited data from clinical observations and studies in experimental animals. Infants born to seropositive mothers are passively immunized by antiviral antibodies acquired transplacentally and via breast milk including neutralizing antibodies, yet, are consistently infected following epithelial exposure to virus present within breast milk. Although these findings might argue that HCMV immunity offers little protection against virus acquisition, since only about half of the infants exposed to HCMV in breast milk will become infected, this model of natural HCMV acquisition provides an unique opportunity to define virologic and immunologic correlates of protection from acquisition of HCMV. By investigating the breast milk transmission of HCMV, we expect to develop a better understanding of the protective antiviral immune responses against mucosal acquisition of HCMV. It is our hypothesis that acquisition of HCMV following exposure of the infant's oral mucosa to HCMV-infected breast milk occurs when inadequate immune control of viral replication or emergence of new viral genome types overcoming the virus-host protective threshold required to prevent transmission. Delineation of the mechanisms leading to this breech of protective antiviral immunity will lead to a more rational design of immunogens capable of inducing protective immunity to HCMV. The goals of the project are to determine the quantity, specificity, and function of HCMV-specific antibodies in maternal breast milk and infant saliva, and the HCMV genome variability patterns associated with lower viral load and antiviral antibodies in these fluids and protection from HCMV breast milk transmission over the first 6 months after delivery.